The objective of this research is to study certain new drugs or new drug/radiation protocols for their effectiveness in achieving hematopoietic cell ablation prior to transplantation therapy of leukemia. At present leukemia recurrence in man following transplantation models is unacceptably high, and attempts at improving the situation by direct alteration of drug/radiation regimens in the clinic have proven repeatedly to be unsuccessful. We propose to approach the problem systematically in a new leukemic mouse model for transplantation therapy which has been developed by our group. This model consists of a leukemia sensitive mouse strain in which the disease is induced by injection of leukemia virus, and which is used as the therapy recipient, and of a histocompatible leukemia resistant F1-hybrid used as the narrow donor. Testing of the effectiveness of the drug/radiation treatment for transplantation therapy and the reduction of leukemia recurrence will involve a stepwise screening process. The first step will be a direct evaluation of the treatment's ability to eliminate hematopoietic stem cells in normal and leukemic mice. This will be done by evaluation of the survival of endogenous hematopoietic stem cells, transplantable CFU-S, and CFU-C after drug and radiation exposure of the whole animal. Those treatment regimens which are found most effective at this step will be further screened for other toxic side-effects and then put to the critical test in a transplantation therapy situation using the mouse model. The transplanted leukemic mice will be observed for: long-term survival, leukemia recurrence, and death due to other than leukemic causes. White blood counts and smears, as well as autopsy examination will be used to confirm leukemia recurrence. Source of the cells involved in the recurrence (host or donor) will be verified by chromosome analysis. Animals dying from other than leukemia will be checked for toxic effects of the protocol on other tissues, particularly intestine. The goal is to achieve in the model minimal leukemia recurrence and toxic side-effects, and to provide a bank of basic information from which clinicians can later draw in designing new narrow ablation protocols for transplantation therapy of human leukemia.